title: Primary resistance of CCR5-tropic HIV-1 to maraviroc cannot be predicted by the V3 sequence.
abstract: OBJECTIVE
  Resistance of HIV-1 to CCR5 antagonists can occur without coreceptor switching by mutations in envelope glycoproteins that enable virus entry using the inhibitor-bound form of CCR5. We investigated whether mutations in the V3 region of HIV-1 from subjects naive to maraviroc could be associated with primary resistance to this drug.
  
  
  METHODS
  The frequency of CCR5-tropic HIV-1 subtype B isolates harbouring putative V3 maraviroc resistance mutations was assessed among the HIV tropism database of Toulouse University Hospital, France. Phenotypic assessment of maraviroc susceptibility was performed for 14 isolates representative of the main mutation patterns and 14 controls. V3 mutations were reversed or introduced by site-directed mutagenesis.
  
  
  RESULTS
  Ninety-three of 951 (9.8%) isolates harboured V3 mutations assumed to be associated with maraviroc resistance. Maraviroc completely blocked virus entry for all but 1 of the 14 isolates harbouring V3 mutations [IC50 8.6 nM; 95% CI (6.6-47.4)], as in the 14 control isolates [IC50 13.4 nM; 95% CI (7.7-50.3)] (P = 0.24). Primary resistance to maraviroc, with a plateau in entry inhibition, was found in one isolate (harbouring a 20F/21I genotype). Site-directed mutagenesis showed that V3 mutations are necessary but not sufficient to induce maraviroc resistance.
  
  
  CONCLUSIONS
  The impact of V3 mutations depended on the env context in which they occurred. Simple assessment of the V3 genotype thus cannot accurately predict maraviroc resistance. Rather, phenotypic assessment of virus particles expressing the envelope glycoprotein as a whole is required. This approach revealed that primary resistance of CCR5-tropic HIV-1 subtype B isolates to maraviroc seems uncommon.
authors.affiliation: INSERM, UMR1043, Toulouse F-31000, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Delobel
authors.forename: Michelle
authors.initials: M
authors.lastname: Cazabat
authors.forename: Adrien
authors.initials: A
authors.lastname: Saliou
authors.forename: Claire
authors.initials: C
authors.lastname: Loiseau
authors.forename: Lucile
authors.initials: L
authors.lastname: Coassin
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Raymond
authors.forename: Mary
authors.initials: M
authors.lastname: Requena
authors.forename: Bruno
authors.initials: B
authors.lastname: Marchou
authors.forename: Patrice
authors.initials: P
authors.lastname: Massip
authors.forename: Jacques
authors.initials: J
authors.lastname: Izopet
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D003510:Cyclohexanes / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D005602:France; D015699:HIV Envelope Protein gp120 / Q000235:genetics*; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D020128:Inhibitory Concentration 50; D000077592:Maraviroc; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D003510:Cyclohexanes; D015699:HIV Envelope Protein gp120; D014230:Triazoles; C514793:gp120 protein, Human immunodeficiency virus 1; D000077592:Maraviroc
keywords: HAART; env; maraviroc; drug resistance; receptors